Interleukin-27 promotes CD8+ T cell reconstitution following antibody-mediated lymphoablation

Ayasoufi, Katayoun; Zwick, Daniel B.; Fan, Ran; Hasgur, Suheyla; Nicosia, Michael; Gorbacheva, Victoria; Keslar, Karen; Min, Booki; Fairchild, Robert L.; Valujskikh, Anna

doi:10.1172/jci.insight.125489

Cited by 17 publications

(23 citation statements)

References 64 publications

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“…RNA samples were prepared from spleen B220 + cells isolated by EasySep immunomagnetic B cell isolation kit. Reverse transcription and quantitative real‐time polymerase chain reaction (PCR) were performed as previously described 14 . Probes and primers were from Taqman gene expression assay reagents (Applied Biosystems, Foster City, CA): IL‐1β (Mm00434228_m1) and IL‐6 (Mm00446190_m1).…”

Section: Methodsmentioning

confidence: 99%

B cell–derived IL-1β and IL-6 drive T cell reconstitution following lymphoablation

Hasgur

Fan

Zwick

et al. 2020

American Journal of Transplantation

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Understanding the mechanisms of T cell homeostatic expansion is crucial for clinical applications of lymphoablative therapies. We previously established that T cell recovery in mouse heart allograft recipients treated with anti‐thymocyte globulin (mATG) critically depends on B cells and is mediated by B cell–derived soluble factors. B cell production of interleukin (IL)‐1β and IL‐6 is markedly upregulated after heart allotransplantation and lymphoablation. Neutralizing IL‐1β or IL‐6 with mAb or the use of recipients lacking mature IL‐1β, IL‐6, IL‐1R, MyD88, or IL‐6R impair CD4+ and CD8+ T cell recovery and significantly enhance the graft‐prolonging efficacy of lymphoablation. Adoptive co‐transfer experiments demonstrate a direct effect of IL‐6 but not IL‐1β on T lymphocytes. Furthermore, B cells incapable of IL‐1β or IL‐6 production have diminished capacity to mediate T cell reconstitution and initiate heart allograft rejection upon adoptive transfer into mATG treated B cell deficient recipients. These findings reveal the essential role of B cell–derived IL‐1β and IL‐6 during homeostatic T cell expansion in a clinically relevant model of lymphoablation.

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Section: Methodsmentioning

confidence: 99%

B cell–derived IL-1β and IL-6 drive T cell reconstitution following lymphoablation

Hasgur

Fan

Zwick

et al. 2020

American Journal of Transplantation

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“…22 promotes the memory phenotype of expanding T cells during homeostatic proliferation, but blocking the IL-27 receptor prevents the expansion of any T cells after depletion in mouse models. 27 Finally, they go on to show that the cytokine production by B cells is the critical component to CD8 T-cell reconstitution following depletion by mATG.…”

Section: Homeostatic Proliferation Following Lymphodepletionmentioning

confidence: 99%

“…Finally, they go on to show that the cytokine production by B cells is the critical component to CD8 T-cell reconstitution following depletion by mATG. 27…”

Section: Homeostatic Proliferation Following Lymphodepletionmentioning

confidence: 99%

Memory T‐cell exhaustion and tolerance in transplantation

Hartigan

Sun

Ford

2019

Immunological Reviews

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One of the biggest barriers to achieving allograft tolerance is the presence of immunological memory within the recipient, which confers a faster, more robust immune response that is in most cases more resistant to pharmacologic immunosuppression. This review will identify the mechanisms by which alloreactive T cells arise within hosts prior to transplantation, and explore the properties of immunological memory that contribute to allograft rejection. In doing so we will also illuminate how targeting pathways that induce memory T cell exhaustion can promote allograft tolerance.Recent studies demonstrating the impact of the allograft microenvironment on memory cell survival and activation, as well as new therapeutic strategies that are being explored to mitigate memory driven allograft rejection, will also be reviewed. K E Y W O R D Scostimulation blockade, exhaustion, T-cell memory, tolerance, transplant

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“…Therefore, molecular markers expressed on T cells or macrophages may be used as a unique biomarker that indicates acute rejection. Recently it was reported that IL-27Rα, the specific subunit of the IL-27 receptor, highly expressed on T cells and macrophages, participates in a variety of inflammatory diseases [11][12][13][14]. Data revealed that over-expression of IL-27Rα increased CD8 + T cell recovery in heart allotransplantation mice treated with an immunosuppressant [11].…”

Section: Introductionmentioning

confidence: 99%

“…Recently it was reported that IL-27Rα, the specific subunit of the IL-27 receptor, highly expressed on T cells and macrophages, participates in a variety of inflammatory diseases [11][12][13][14]. Data revealed that over-expression of IL-27Rα increased CD8 + T cell recovery in heart allotransplantation mice treated with an immunosuppressant [11]. Blocking the IL-27 pathway prevented graft-versus-host disease (GVHD) [15], which suggested that IL-27 accelerates acute rejection.…”

Section: Introductionmentioning

confidence: 99%

IL-27Rα: A Novel Molecular Imaging Marker for Allograft Rejection

Zhao

Shi

et al. 2020

IJMS

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Non-invasively monitoring allogeneic graft rejection with a specific marker is of great importance for prognosis of patients. Recently, data revealed that IL-27Rα was up-regulated in alloreactive CD4+ T cells and participated in inflammatory diseases. Here, we evaluated whether IL-27Rα could be used in monitoring allogeneic graft rejection both in vitro and in vivo. Allogeneic (C57BL/6 donor to BALB/c recipient) and syngeneic (BALB/c both as donor and recipient) skin grafted mouse models were established. The expression of IL-27Rα in grafts was detected. The radio-probe, 125I-anti-IL-27Rα mAb, was prepared. Dynamic whole-body phosphor-autoradiography, ex vivo biodistribution and immunofluorescence staining were performed. The results showed that the highest expression of IL-27Rα was detected in allogeneic grafts on day 10 post transplantation (top period of allorejection). 125I-anti-IL-27Rα mAb was successfully prepared with higher specificity and affinity. Whole-body phosphor-autoradiography showed higher radioactivity accumulation in allogeneic grafts than syngeneic grafts on day 10. The uptake of 125I-anti-IL-27Rα mAb in allogeneic grafts could be almost totally blocked by pre-injection with excess unlabeled anti-IL-27Rα mAb. Interestingly, we found that 125I-anti-IL-27Rα mAb accumulated in allogeneic grafts, along with weaker inflammation earlier on day 6. The high uptake of 125I-anti-IL-27Rα mAb was correlated with the higher infiltrated IL-27Rα positive cells (CD3+/CD68+) in allogeneic grafts. In conclusion, IL-27Rα may be a novel molecular imaging marker to predict allorejection.

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Interleukin-27 promotes CD8+ T cell reconstitution following antibody-mediated lymphoablation

Cited by 17 publications

References 64 publications

B cell–derived IL-1β and IL-6 drive T cell reconstitution following lymphoablation

B cell–derived IL-1β and IL-6 drive T cell reconstitution following lymphoablation

Memory T‐cell exhaustion and tolerance in transplantation

IL-27Rα: A Novel Molecular Imaging Marker for Allograft Rejection

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